Trying to watch the tutorial videos, I've found out that the link to n° 4: Applying subheadings (https://www.nlm.nih.gov/bsd/viewlet/mesh/subheadings/mesh3.html) does not work.
If you needed, here's a youtube video explaining the procedure:

https://www.youtube.com/watch?v=LTtrvUQLsWo

I hope it will be a help to you!

To be honest it was not so easy as it might seem to use PubMed as a tool search, but I have experimented different combinations until I was quite satisfied with results, also using the MeSH function. 

Searching information about ELQ-300 I have not found a lot, instead of searching about other drug's therapy in cases of cerebral malaria there were more results.

In particular which related with Glutamine and analogue of it, that could revers this type of infection. 

Even if not on my research I also found about the risk of a diet with an high use of folate - which consumption has increased in many population - because in a murine model of cerebral malaria high dietary folate would affect response to malarial infection. 

At the beginning, doing a search on PubMed hasn't been as easy as you may think: we are used to surf on Google or Yahoo in a very simple and intuitive way. Video tutorials have been very helpful, but a lot of practice is required, in order to optimize the results and improve our own skills.

I have constructed my free text search applying PICO technique and Boolean operators; I also used suitable filters, and tried different combination, helping myself with the MeSH database. I experienced a MeSH search using subheadings and hierarchy terms, then choosing the fittest ones and adding them to the Search Builder: it hasn't been that easy.

In my opinion, patients don't have this kind of skills, and in the most part of the cases they ignore PubMed's existence. They do researches about their medical problems on the Web, but it could be dangerous and distorting; the most part of common results is not supported by scientific studies.

I have refused to treat my skin disease with Isoriac (isotretinoin-based drug) for many years, because I read about its terrible adverse effects on the Web: I was really afraid. I solved my problem only after trusting the dermatologist, who advised me this drug, also reassured me on the possible adverse effects, thanks to her studies on clinical evidence and medical experience.

The advise of a doctor must always be the most important thing for a patient.

I was not able to use PubMed! Thanks to the tutorial videos, I have learnt a lot. I'm honest: I still have problems with MeSh database and its subheadings, but I'll exercise myself. I think PubMed is fantastic! I can find all the medical information I need and with limits and filters the search is really easy.

I've searched information about cerebral malaria and ELQ-300, using PICO and MeSH and some filters. Firstly, I have found not many information because of the filters!!! Indeed, I have searched for systematic reviews or randomized-clinical trials! Then, without these filters, I have found that ELQ-300 is a preclinical candidate in  a combination therapy with Atovaquone for antimalarial therapy. Their target is the cytochrome bc1 complex (cyt bc1). So, this drug therapy, based on ELQ-300, has not a medical evidence, yet.

At first it was not easy for me to use PubMed, but the tutorial videos have helped me a lot... indeed it is required a lot of practice! 

However I've firstly searched for ''cerebral malaria treatment'' and, as first result, I've found that there is an intramuscular arteether-vitamin D (ART-VD) combination treatmen which is very good to cure malaria; instead I've not found many results about ELQ-300. Then I've written ''ELQ-300'' and I've finally found something. I've discovered that ELQ-300 is combinated with ATV (atovaquone) and this treatment successfully blocked recrudescence even in a high parasitemia, so it's very powerful!

PubMed is a very good site in which everyone can find certain results about their researches. But I think it's not so easy for common people to search here for two reasons: first of all there are very scientific results which maybe common people don't understand easily (that's one of the reason why people prefer searching about pathologies and treatements on google than on scientific site); and the second reason is that PubMed is not easy to use. However with some practice everybody should learn to use this site!

I personally found the research on pubmed quite complicated . But in the end I managed to risolve exercise researching the keywords of the problem ( ELQ- 300 ) . There are many interesting articles , other related to specific diseases , and others who responded to my questions . Items found were quite sufficient to my request specifying the clinical case and the treatments in both children and adults .

Pubmed is considered a medical encyclopedia where people can have a lot of informations on various medical problems. It is difficult to use pubmed, but through the tutorial videos I understand how the search should be conducted and how to reduce the number of results after entering the various limits to get to a reasonable number of articles. 

At the beginning is not easy to research with PubMed as you may think. We are used to surf the internet in a very simple way; we ask and Google answers. Instead, for a software as PubMed, a studied research is needed. I suppose that no patient does a that difficult research on this complicate site. So they only surf the internet founding dangerous and false information. I did my research about cerebral malaria and ELQ-300; I found a few information. Doing various attempts I understood that the filters limited my survey. Once I removed the filters I managed to understand the role of ELQ-300 combined with another drug (Atovaquone) for antimalarial therapy. I also found that this therapy has not medical evidence yet.

I've searched on PubMed some info with these keywords: (malaria) AND (ELQ-300), and I've had some results. There's an interesting article that describes the atovaquone and ELQ-300 combination therapy as a dual-site cytochrome bc1 inibition strategy to fight malaria. This combination therapy also prevent a possible drug-resistant on Plasmodium.

At first sight, it could seem a bit difficult to search something using PubMed because there are so many information and abstract collected that it is relevant to be able to select the key worlds we really need to find the answer to our question. Watching tutorial videos is an easy way to understand the main functions of PubMed so after doing it and after some practice i managed to search what I wanted like, for example, informations about ELQ-300,the new drug against Malaria symptoms.

I started following tutorials and the examples and then I made my search on PubMed to analyze the clinical case of the african girl and the ELQ-300. I found that this is an important therapy against Plasmodium parasites. It is bound to ATV (atovaquone), another drug. 

I found that the inhibitors of the mitochondrial cytochrome bc1 complex are effective for both anti-malarian treatment and prophylaxis. Anyway ELQ-300 is still in a testing phase.

PubMed is very useful! You can find everything about medicine, even if I had some difficult to understand how using it.  

I started completing the table with key words: in particular cerebral malaria and the drug ELQ-300.

Then i used MeSH to link these key words and serach them on PubMed. The best article that i found was about the use of this drug in combination with ATOVAQUONE (ATV), as an inibition strategy againts Plasmodium, in particulare stopping cytochrome bc1

It was hard at the beginning using PubMed and choose the right key words to search with.

First of all I tried to use the PICO method with different words, but I didn't found any results, so I tried to look for information about ELQ-300 (also with MeSH's help), but I didn't found anything on PubMed. Then I searched infos about treatment for cerebral malaria using filters as "published in the last 5 years" and "free full text".

I found out that there are some studies about a genetic therapy which consists in CXCL10 neutralization or genetic deletion of its gene. This process seems to alleviate brain intravascular inflammation and protects Plasmodium berghei ANKA-infected mice from CM (cerebral malaria).

Source:

Ioannidis LJ, Nie CQ, Ly A, Ryg-Cornejo V, Chiu CY, Hansen DS (2016) Monocyte- and Neutrophil-Derived CXCL10 Impairs Efficient Control of Blood-Stage Malaria Infection and Promotes Severe Disease. J immunol 196(3):1227-38

At first, PubMed seems to be a really complicated search engine. There are many things to consider in order to find what you really need. There are so many abstracts, data and informations collected in the database from which you can choose. You also have to be able to pick the right key words to use for your research. The tutorial videos are really helpful to start exploring PubMed. With time and "practice" I learn how to use PubMed and its functions a little better. This allowed me to search for further informations about a new drug used in patients with Malaria to "fight" the symptoms of the disease, ELQ-3000.

After following the pubmed video tutorials I tried to do my research with PICO technique. I verify that it's not easy searching on pubmed in this way. After several attempts I improved the technique and I Must admit that it greatly restricts the search field.

To search PubMed for ELQ-300’s effect on cerebral malaria, I used some filters (published in the last 5 years, free full text) and the key words “malaria AND child* AND therapy AND ELQ-300” and I got only one result: it was a 2013 research claiming ELQ-300 (a quinolone-3-diarylether) “ has potential as a new drug for the treatment, prevention, and, ultimately, eradication of human malaria”⁴. Although, it still is in a preclinical phase, so there’s no scientific evidence yet.

Erasing the word “child*” I got 4 results. The most interesting one claims that “ELQ-300 represent valuable partner drugs for the clinically successful Qo site inhibitor ATV”⁵; ATV is “atovaquone”, which  is an inhibitor of the parasite’s mitochondrial cytochrome bc1 complex (cyt bc1).

I mainly used the PICO technique, even though MeSH was useful as well.   

References:

4.        Nilsen, A. et al. Quinolone-3-diarylethers: a new class of antimalarial drug. Sci. Transl. Med. 5, 177ra37 (2013).

5.        Stickles, A. M. et al. Atovaquone and ELQ-300 Combination Therapy as a Novel Dual-Site Cytochrome bc1 Inhibition Strategy for Malaria. Antimicrob. Agents Chemother. 60, 4853–4859 (2016).

At first I tried searching (cerebral malaria) AND (ELC 300), but there were no results so I tried expand the search and looked for (malaria) AND (ELC 300) than I found 6 results. when I tried to add filter of age such as 0-18  years there were no results again..

To search on PubMed about the efficacy of ELQ-300 to treat cerebral malaria, I used PICO and I typed (child) AND (ELQ-300) AND (malaria) AND (prognosis OR recovery) and, after applying the filter of 5 years, I got 5 results. I read the all five and I selected the most interesting article dated 2015, claiming that "ELQ-300 is a preclinical candidate that targets the liver and blood stages of Plasmodium falciparum, as well as the forms that are crucial to transmission of disease. A significant obstacle to the clinical development of ELQ-300 is related to its physicochemical properties..."

The drug “ELQ-300” is a member of the “quinolones” which also includes quinine, the most commonly used anti-malaria treatment.  Searching on PubMed what I find  most interesting  is not so much its use as an anti-malaria drug, which has been tested (there is a article published in 2003 showing good evidence in the pre-clinical stage of the study) but the possibility of using it  together with atovaquone (ATV) which  is an inhibitor of the parasite’s mitochondrial cytochrome bc1 complex (cyt bc1) and ELQ-300 which inhibits the quinone reductase (Qi) site and retains full potency against ATV-resistant Plasmodium falciparum strains with Qo site mutations. In the animal model, the latest  data show that this combined therapy could decrease the development of drug-resistant Plasmodium parasites.

I searched on PubMed using PICO. I used "child, malaria, ELQ-300, drug therapy, therapy, reduce risks, reduce seizures, recovery" as key words in two different combinations. 

The first combination was: child AND drug therapy AND malaria AND (recovery OR reduce seizures); limits: 5 years, Human.

The second combination was: malaria AND ELQ-300 AND therapy

I examined the results of both searches and I found out the most interesting evidence in one dated 2015 by Miley GP1 et all. According to this study ELQ-300 targets the liver and blood stages of Plasmodium Falciparum, as well as gametocytes, zygotes and ookinetes but there is a significant obstacle to its development related to physicochemical properties. ELQ-300 has poor aqueous solubility and high crystallinity limits absorption and so low blood concentrations are sufficient for therapy but their levels are too low to have an acceptable safety margin as required by regulatory agiences for clinical development. 

A bioreversible O-linked carbonate ester prodrug of the parent molecule, ELQ-337, was profiled to address the challenging physicochemical properties of ELQ-300.The prodrugs ELQ-337 is a viable approach to deliver the active drug to the bloodstream at concentrations sufficient for safety and toxicology studies.

References: 

1. Miley GP, Pou S, Winter R, Nilsen A, Li Y, Kelly JX, Stickles AM, Mather MW, Forquer IP, Pershing AM, White K, Shackleford    D, Saunders J, Chen G, Ting LM, Kim K, Zakharov LN, Donini C, Burrows JN, Vaidya AB, Charman SA, Riscoe MK. ELQ-300 prodrugs for enhanced delivery and single-dose cure of malaria.Antimicrob Agents Chemother. 2015 Sep;59(9):5555-60. doi: 10.1128/AAC.01183-15. Epub 2015 Jun 29.

Doing a search on PubMed is not as simple as it sounds: I initially searched for "(child) AND (ELQ-300) AND (malaria) AND (recovery OR survival)" but without results. So then I searched "(ELQ-300) AND (malaria)" finding 6 articles: filtering them with "All child" remained 0, while with "published in the last 5 years" there were 5.

After reading them all I chose the most interesting one in which it is claimed that "ELQ-300 is a preclinical antimalarial drug candidate that is active against liver, blood, and transmission stages of Plasmodium falciparum. While ELQ-300 is highly effective when administered in a low multidose regimen, poor aqueous solubility and high crystallinity have hindered its clinical development.” So they are trying to develop bioreversible prodrugs that are converted to ELQ-300 by host and parasite esterase action with improved physiochemical and metabolic properties and excellent potential for clinical formulation.¹

 

REFERENCES

1.        Frueh, L. et al. Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria. ACS Infect. Dis. 3, 728–735 (2017).

 

 

I have searched on pubmed, using PICO technique, and so I have typed (Malaria) AND (ELQ-300) AND (Therapy) AND (Survival OR Safety) and I have read 3 abstracts, that I think were the most interesting. These abstracts talk about ELQ-300 as a preclinical antimalarial drug candidate that is active against liver, blood, and transmission stages of Plasmodium falciparum. The trials show that the  ELQ-300 prodrug strategy represents a viable approach to overcome the physicochemical limitations of ELQ-300 to deliver the active drug to the bloodstream at concentrations sufficient for safety and toxicology studies, as well as achieving single-dose cures. For example an abstract talks about ELQ-331 that is a promising prodrug of ELQ-300 with improved physiochemical and metabolic properties and excellent potential for clinical formulation. An other strategy showed is the atovaquone and ELQ-300 combination therapy as a novel dual-site cytochrome bc1 inhibition.

At first I searched "malaria" AND "ELQ-300" AND "therapy" AND "safety", but I didn't find anything. Then I searched "malaria" AND "ELQ-300" and I found some interesting articles about this drug. One the most recent was written in 2017 by Frueh and it says that it is a preclinical antimalarial drug active agaist blood, liver and transmission stages. Its effectiveness was hindered by its poor aqueous solubility and high cristallinity, but then some prodrugs have been developed. It his highly effective in a low multidose regimen

Searching child celebral malaria ELQ -300 , I found 0 results; then I removed the word celebral: 0 results too! Then I removed the word child and Pubmed showed me some reults; the best one was from L.Frueh. He states that ELQ-300 is a preclinical antimalarial drug candidate that is active against liver, blood, and transmission stages of Plasmodium falciparum, so it is not useful for an alraeady hill child.

REFERENCES

1.        Frueh, L. et al. Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria. ACS Infect. Dis. 3, 728–735 (2017).

I do a first research on Pubmed under these keywords: cerebral malaria- ELQ 300- atovaquone, reduce risk  but didn’t made up any results. I made an other search under the words PLASMODIUM - ELQ 300  and i found  5 results each one published from 2013. A cause of the advantage stade of the pathology the only article that could be useful for this patient is this one that talking about a co-action of ELQ-300 and ATOVAQUONE against drug-resistant Plasmodium parasites. These two drugs act as inhibitors of the mitochondrial cytochrome bc1 complex (cyt bc1)  that are effective for acute antimalarial treatment and prophylaxis. There are two known sites for inhibition within cyt bc1: atovaquone (ATV) blocks the quinol oxidase (Qo) site of cyt bc1, while some members of the endochin-like quinolone (ELQ) family, including preclinical candidate ELQ-300, inhibit the quinone reductase (Qi) site and retain full potency against ATV-resistant Plasmodium falciparum strains with Qo site mutations. ELQ-300 is a preclinical candidate that targets the liver and blood stages of Plasmodium falciparum, as well as the forms that are crucial to transmission of disease: gametocytes, zygotes, and ookinetes. A significant obstacle to the clinical development of ELQ-300 is related to its physicochemical properties. Its relatively poor aqueous solubility and high crystallinity limit absorption to the degree that only low blood concentrations can be achieved following oral dosing. While these low blood concentrations are sufficient for therapy, the levels are too low to establish an acceptable safety margin required by regulatory agencies for clinical development. One way to address the challenging physicochemical properties of ELQ-300 is through the development of prodrugs. Here, we profile ELQ-337, a bioreversible O-linked carbonate ester prodrug of the parent molecule. Our findings show that the prodrug strategy represents a viable approach to overcome the physicochemical limitations of ELQ-300 to deliver the active drug to the bloodstream at concentrations sufficient for safety and toxicology studies, as well as achieving single-dose cures. From these two research we could find a solution for patient problem, probably a therapy based on the use of each these three drugs may be product a reduction of the risks  derived from the only use of ELQ 300 and  against drug-resistant Plasmodium parasites.

References:

1)Stickles AM, Smilkstein MJ, Morrisey JM, Li Y, Forquer IP, Kelly JX, Pou S, Winter RW, Nilsen A, Vaidya AB, Riscoe MK.

2)Miley GP, Pou S, Winter R, Nilsen A, Li Y, Kelly JX, Stickles AM, Mather MW, Forquer IP, Pershing AM, White K, Shackleford D, Saunders J, Chen G, Ting LM, Kim K, Zakharov LN, Donini C, Burrows JN, Vaidya AB, Charman SA, Riscoe MK

I searched

ELQ-300; MALARIA AND ELQ-300;

AND ATOVAQUONE; MALARIA AND ELQ.

FILTERS: LAST 5 YEARS ; HUMANS

From the abstracts:

“Quinolones, such as the antimalarial atovaquone, are inhibitors of the malarial mitochondrial cytochrome bc 1  complex, a target critical to the survival of both liver- and blood-stage parasites, making these drugs useful as both prophylaxis and treatment”. “the combination of the novel quinolone ELQ-300 with atovaquone was synergistic against both species (P.FALCIPARUM, P. KNOWELSI)”  “ATOVAQUONE and ELQ-300  works on two known sites for inhibition within cyt bc1: atovaquone (ATV) blocks the quinol oxidase (Qo) site of cyt bc1, while some members of the endochin-like quinolone (ELQ) family, including preclinical candidate ELQ-300, inhibit the quinone reductase (Qi) site and retain full potency against ATV-resistant Plasmodium falciparum strains with Qo site mutations”. “ATV:ELQ-300 therapy was highly synergistic, and the combination was curative with a single combined dose of 1 mg/kg of body weight. Compared to the ATV:proguanil (Malarone) formulation, ATV:ELQ-300 was more efficacious in multiday, acute infection models and was equally effective at blocking the emergence of ATV-resistant parasites.”” “ELQ331 is a promising prodrug of ELQ-300 with improved physiochemical and metabolic properties and excellent potential for clinical formulation”

references

1.         Stickles, A. M. et al. Atovaquone and ELQ-300 combination therapy as a novel dual-site cytochrome bc1 inhibition strategy for malaria. Antimicrob. Agents Chemother. 60, 4853–4859 (2016).

2.        Van Schalkwyk, D. A. et al. Novel endochin-like quinolones exhibit potent in vitro activity against Plasmodium knowlesi but do not synergize with proguanil. Antimicrob. Agents Chemother. 64, (2020).

3.         Frueh, L. et al. Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria. ACS Infect. Dis. 3, 728–735 (2017).

4.            Smilkstein, M. J. et al. ELQ-331 as a prototype for extremely durable chemoprotection against malaria. Malar. J. 18, (2019).

I've researched on Mesh "cerebral malaria" associated to "ELQ-300" but the results was negative, and with more accurate researches such as (ELQ-300) AND (malaria), I've found that ELQ-300 has been studied in murine methods for the treatment of acute malaria, but more utile as prodrug ELQ-331 because has less collateral effects, toxicity and efficience; Its association with atovaquone is useful for the prevenion of the emercenge drug-resistance. Instead on Mesh I've found that cerebral malaria could be healed with an intranasal administration of artesunate.

I did a PubMed search using the following words: 

1. (African child) AND (cerebral malaria) AND (ELQ-300) AND (reduce complications) >>>NO RESULTS

2. (cerebral malaria) AND (ELQ-300) >>> NO RESULTS

3. (malaria) AND (ELQ-300) with filters “in the last 5 years” >>> 6 RESULTS. 

I think these are the most interesting:

1.     Stickles AM, Smilkstein MJ et al, 2016, Atovaquone and ELQ-300 Combination Therapy as a Novel Dual-Site Cytochrome bc1 Inhibition Strategy for Malaria, Antimicrobial agents and chemotherapy, 22;60(8):4853-9

2.    Smilkstein MJ, Pou S et al, 2019, ELQ-331 as a prototype for extremely durable chemoprotection against malaria, Malar Journal, 27;18(1):291 

At first I used this combination(Malaria) AND (ELQ-300) AND (Therapy) AND (Survival OR Safety), and I found an article dated 2015 stating that this compostition could not assure an acceptable safety margin, whereas prodrug strategy represents a viable approach. 

[Miley GP, Pou S, Winter R, et al. ELQ-300 prodrugs for enhanced delivery and single-dose cure of malaria. Antimicrob Agents Chemother. 2015;59(9):5555-5560. doi:10.1128/AAC.01183-15]

Subsetting patient by (cerebral AND malaria) has showed no results, while (malaria) AND (ELQ-300) AND (Survival OR Safety OR effectiveness) showed 9 results. To me, the most useful seems to be the one picturing both a therapeutic and chemoprotective effect of ELQ-331, prodrug from ELQ-300.

[Smilkstein MJ, Pou S, Krollenbrock A, et al. ELQ-331 as a prototype for extremely durable chemoprotection against malaria. Malar J. 2019;18(1):291. Published 2019 Aug 27. doi:10.1186/s12936-019-2921-9]